Fibrin sealants, also known as fibrin glue, have been in use in the clinic for decades (see, for example, Tabélé, et al. J Pharm Pharmaceut Sci 2012, 15:124-140; Dickneite, G et al. Thrombosis Res 2003, 112:73-82). Oftentimes, fibrin sealant consist of two liquid components, a fibrinogen comprising component and a thrombin comprising component, which are stored frozen due to their inherent instability. Sometimes fibrin sealant products consist of two freeze dried components, which require reconstitution immediately prior to use and delivery by a conjoined syringe or other double-barreled delivery device. Freeze dried formulations are typically stable, but the fibrinogen component is difficult to reconstitute.
A fibrin sealant clot is formed by enzymatic reactions involving fibrinogen, thrombin and Factor XIII. The thrombin converts the fibrinogen to fibrin by enzymatic action at a rate determined by the concentration of thrombin. Factor XIII, an enzyme of the blood coagulation system, cross-links and stabilizes the fibrin clot. This process bypasses most of the steps of normal coagulation and mimics its last phase. Some manufacturers add anti-proteolytic agents to the fibrin glue formulation (e.g. as described in WO93/05822) or specifically remove the plasminogen in order to stop or delay fibrinolysis (e.g. as described in U.S. Pat. Nos. 5,792,835 and 7,125,569).
The thrombin component contains the enzyme thrombin, which is a serine protease, and can be from human or animal (e.g. bovine or porcine) origin or recombinantly produced. The fibrinogen component can be from human or animal origin or recombinantly produced. Upon mixing the two-component solutions, thrombin cleaves fibrinogen thus allowing the latter to generate fibrin polymers/sealant.
Thrombin displays high specificity toward fibrinogen and cleaves a defined sequence in the fibrinogen molecule, however, at very high concentrations thrombin can undergo auto-proteolysis. The auto-proteolytic properties of thrombin may result in reduced activity and instability of the thrombin component of fibrin sealant.
Background art includes U.S. Pat. Nos. 5,219,328; 5,318,524; 8,367,802; 6,500,427; 5,750,657; 6,262,236; 6,268,483; and US Patent Application Publication No. 2013/0149292.